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• 452062-33-8 S-(+)-2β-carboethoxy-4',4''-difluoro-3α-(diphenylmethoxy)tropane 

Relevant academic research and scientific papers

Structure-activity relationship studies on a novel series of (S)-2β-substituted 3α-[bis(4-fluoro- or 4-chlorophenyl)methoxy] tropane analogues for in vivo investigation

In general, 3α-(diphenylmethoxy)tropane (benztropine)-based dopamine uptake inhibitors do not demonstrate cocaine-like pharmacological activity in models of psychostimulant abuse and have been proposed as potential medications for the treatment of cocaine addiction. However, several (S)-2-carboalkoxy- substituted-3α-[bis(4-fluorophenyl)methoxy]tropane analogues were discovered to stimulate locomotor activity and substitute in subjects trained to discriminate cocaine, suggesting a role of the 2-position substituent in mediating these cocaine-like actions. Herein, we describe the synthesis of a series of novel N- and 2-substituted-3α-[bis-(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues. Most of these analogues demonstrated high affinity binding to the dopamine transporter (DAT; Ki = 1.8-40 nM), and selectivity over the other monoamine transporters and muscarinic M 1 receptors. When the (S)-2-carboalkoxy substituent was replaced with (S)-2-ethenyl, the resulting analogue 11 demonstrated the highest DAT binding affinity in the series (Ki = 1.81 nM) with DAT selectivity over serotonin transporters (SERT; 989-fold), norepinephrine transporters (NET; 261-fold) and muscarinic receptors (90-fold). When the 4′-F groups of compounds 5 (Ki = 2.94 nM) and 8 (Ki = 6.87 nM) were replaced with 4′-Cl in the (S)-2-carboalkoxy series, DAT binding affinities were slightly reduced (Ki = 12.6 and 14.6 nM for 6 and 7, respectively), yet inhibition of dopamine uptake potency remained comparably high (IC50 range = 1.5-2.5 nM). Interestingly, the 4′-Cl analogue (±)-6 substituted less in rats trained to discriminate cocaine than the 4′-F analogue (±)-5. These studies demonstrate that manipulation of the 2-, N-, and 3-position substituents in the 3α-(diphenylmethoxy)tropane class of dopamine uptake inhibitors can result in ligands with high affinity and selectivity for the DAT, and distinctive in vivo pharmacological profiles that cannot be predicted by their effects in vitro.

BENZTROPINE COMPOUNDS AND USES THEREOF

Disclosed are benztropine analogs having the formula (I) in which Ar is a C6-C20 monocyclic aryl group or a C10-C20 bicyclic aryl group or a heteroaryl, heterocyclic, or arylheterocyclic group having 2 to 12 carbon atoms and one or more heteroatoms selected from the group consisting of N, O, S, P, and any combination thereof; m = 1 to 5; n = 1 to 3; and R1 to R4 are as described in the specification; or a pharmaceutically acceptable salt or solvate thereof; pharmaceutical compositions and use thereof, e.g., in treating mental disorders.